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Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract at any point from the mouth to the rectum. Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia. Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum. Acute phase reactants, such as C-reactive protein level and erythrocyte sedimentation rate, are often increased with inflammation and may correlate with disease activity. Levels of vitamin B12, folate, albumin, prealbumin, and vitamin D can help assess nutritional status. Colonoscopy with ileoscopy, capsule endoscopy, computed tomography enterography, and small bowel follow-through are often used to diagnose Crohn's disease. Ultrasonography, computed axial tomography, scintigraphy, and magnetic resonance imaging can assess for extraintestinal manifestations or complications (e.g., abscess, perforation). Mesalamine products are often used for the medical management of mild to moderate colonic Crohn's disease. Antibiotics (e.g., metronidazole, fluoroquinolones) are often used for treatment. Patients with moderate to severe Crohn's disease are treated with corticosteroids, azathioprine, 6-mercaptopurine, or anti–tumor necrosis factor agents (e.g., infliximab, adalimumab). Severe disease may require emergent hospitalization and a multidisciplinary approach with a family physician, gastroenterologist, and surgeon.

Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract characterized by inflammation at any point from the mouth to the rectum (Table 1). The prevalence in the United States is 201 per 100,000 adults.1 Patients with Crohn's disease often present in adolescence, and the median age at diagnosis is 20 to 30 years.2 Crohn's disease is more prevalent in women than men, in developed countries, and in the northern hemisphere.1,2 The annual U.S. economic burden of Crohn's disease is estimated to be $10.9 to 15.5 billion in 2006 U.S. dollars.3

Although the etiology of Crohn's disease is unknown, it is associated with a mutation on the NOD2 gene.4 Smoking and use of oral contraceptives and nonselective nonsteroidal anti-inflammatory drugs are associated with exacerbation of symptoms.5–7

HISTORY AND PHYSICAL EXAMINATION

Common symptoms of Crohn's disease include abdominal pain, diarrhea, fatigue, fever, gastrointestinal bleeding, and weight loss. The history should address the onset, severity, and pattern of symptoms, especially frequency and consistency of bowel movements. History targeting risk factors and possible alternative diagnoses includes recent travel, exposure to antibiotics, food intolerance, medications, smoking, and family history of inflammatory bowel disease8(Table 39). Specific questions addressing extraintestinal manifestations include eye and joint problems and symptoms of anemia (Table 4).10 Questions about the impact of symptoms should include time missed from school or work.

During the physical evaluation, heart rate, blood pressure, temperature, and body weight should be measured.8 Abdominal examination may reveal tenderness, distention, or masses.8 An anorectal examination should be performed because one-third of patients have a perirectal abscess, fissure, or fistula at some time during the illness.11

ENDOSCOPY AND RELATED INVESTIGATIONS

Colonoscopy with ileoscopy and biopsy is valuable in the diagnosis of Crohn's disease at the junction of the ileum and colon8(Figure 1). Characteristic endoscopic findings include skip lesions, cobblestoning (Figure 2), ulcerations, and strictures. Histology may show neutrophilic inflammation, noncaseating granulomas, Paneth cell metaplasia, and intestinal villi blunting. Other diagnostic tests useful in the diagnosis of small bowel Crohn's disease include capsule endoscopy, computed tomography enterography (Figure 3), magnetic resonance enterography, and small bowel follow-through (Tables 716and 8). Capsule endoscopy should be avoided in patients with small bowel strictures because capsule retention may occur. Esophagogastroduodenoscopy is recommended in patients with upper gastrointestinal symptoms; asymptomatic patients with iron deficiency anemia; and patients with active Crohn's disease who have a normal colonoscopy.8

Gross anatomical specimen from a patient with ileocolonic Crohn's disease. Note the sharp demarcation between the cobblestone mucosa of the involved segment and the grossly normal ileal and colonic mucosae.

Figure 2.

Gross anatomical specimen from a patient with ileocolonic Crohn's disease. Note the sharp demarcation between the cobblestone mucosa of the involved segment and the grossly normal ileal and colonic mucosae.

Active Treatment

Therapeutic recommendations are determined by disease location, activity, and severity, and by disease-associated complications. The goals of therapy are control of symptoms, induction of clinical remission, and maintenance of remission with minimal adverse effects.17 Two principal strategies are currently used for Crohn's disease management. A traditional “step-up” approach begins with corticosteroids or mesalamine products and advances to immunomodulators or anti–tumor necrosis factor (TNF) agents based on severity of disease (Table 9). A “top-down” approach begins with anti-TNF agents. The optimal treatment strategy remains controversial.

MILD DISEASE ACTIVITY

Patients with mild disease activity and no systemic symptoms are ambulatory and able to tolerate oral diet and medications.8

Mesalamine Products. Sulfasalazine (Azulfidine) and 5-aminosalicylic acid (5-ASA) are often used in the medical management of mild to moderate colonic Crohn's disease (Table 11). Sulfasalazine can cause nausea, headache, fever, rash, male infertility, and rarely agranulocytosis, which usually occurs within the first two months of therapy. 5-ASA is believed to have anti-inflammatory and immunosuppressive properties. 5-ASA products are well tolerated and are preferred to sulfasalazine because they have fewer adverse effects. Headache, nausea, diarrhea, and abdominal pain may occur with 5-ASA. Pancreatitis or pneumonitis may occur with sulfasalazine and mesalamine.

‡—Price based on information obtained at http://www.pillbot.com (accessed July 18, 2011).

Antibiotics. Antibiotics, especially metronidazole (Flagyl) and ciprofloxacin (Cipro), are widely used and can have both anti-inflammatory and anti-infectious properties. Controlled trials have not consistently demonstrated effectiveness.19,20

Budesonide. Budesonide (Entocort EC) is an oral, controlled-release glucocorticoid that is useful for treating Crohn's disease at the junction of the ileum and colon or ascending colon. A Cochrane review found that budesonide was more effective than placebo (relative risk [RR] = 1.96; 95% CI, 1.2 to 3.2) or mesalamine (RR = 1.63; 95% CI, 1.2 to 2.2) for induction of remission in patients with Crohn's disease.21

MODERATE DISEASE ACTIVITY

Outpatients with moderate disease activity are defined by failed treatment for mild disease or by fever, weight loss, abdominal pain, nausea or vomiting without obstruction, or anemia.8 Many of these patients are treated by gastroenterologists.

Corticosteroid Therapy. Patients with moderate to severe Crohn's disease are treated with prednisone until improvement of symptoms. Corticosteroids are more effective than placebo (RR = 1.99; 95% CI, 1.51 to 2.64; P < .00001) and 5-ASA products (RR =1.65; 95% CI, 1.33 to 2.03; P < .00001) at inducing remission in patients with Crohn's disease.22 If symptoms are not controlled with adequate doses of prednisone, urgent gastroenterology consultation is warranted. No standards have been established for corticosteroid tapering; however, reduction by 5 to 10 mg per week to 20 mg and then by 2.5 to 5 mg per week until discontinuation is reasonable.

Azathioprine and 6-Mercaptopurine. Azathioprine (Imuran) and 6-mercaptopurine can effectively induce remission in patients with active Crohn's disease within three to six months of achieving the maximal dose (OR = 2.5; 95% CI, 1.6 to 3.9; number needed to treat [NNT] = 5).23 These agents are primarily used for long-term maintenance of remission and are typically combined with corticosteroids or occasionally with anti-TNF preparations. Routine monitoring of white blood cell count, platelet count, and hemoglobin and creatinine levels is recommended.24 Adverse effects of azathioprine and 6-mercaptopurine include leukopenia, thrombocytopenia, bone marrow suppression, immunosuppression, pancreatitis, hypersensitivity reaction, lymphoma, nausea, vomiting, elevated liver enzymes, and fever.

Anti-TNF Agents. Three TNF antagonist (anti-TNF) therapies (infliximab [Remicade], adalimumab [Humira], and certolizumab pegol [Cimzia]) are approved by the U.S. Food and Drug Administration for moderate to severe Crohn's disease. Anti-TNF therapy may be considered in patients with moderate to severe active Crohn's disease that does not respond to corticosteroids or immunosuppressive therapy. It is also used for patients in whom corticosteroids are contraindicated or not desired. Relative or absolute contraindications to anti-TNF therapy include sepsis, tuberculosis, optic neuritis, infusion reaction, and cancer. A negative purified protein derivative test and chest radiography before treatment with anti-TNF agents are important because this therapy is associated with reactivation of tuberculosis.27 Anti-TNF therapy has been shown to effectively induce and maintain remission in patients with moderate to severe Crohn's disease.24,28,29

SEVERE DISEASE ACTIVITY

Patients with severe disease activity have persistent symptoms despite therapy, or they present with fever, vomiting, evidence of intestinal obstruction, involuntary guarding or rebound tenderness, cachexia, or evidence of abscess. These patients require emergent hospitalization and gastroenterology consultation.8 Evaluation often includes abdominal imaging and laboratory tests, including a complete blood count, complete metabolic panel, blood cultures, urinalysis, urine culture, stool culture, and C. difficile stool antigen test. Computed tomography or magnetic resonance enterography may differentiate inflammatory from fibrotic strictures. Urgent surgical evaluation is recommended for patients with symptoms of intestinal obstruction or abdominal mass. An abscess requires percutaneous or open surgical drainage. Fluid resuscitation, parenteral corticosteroids, and broad-spectrum antibiotics should be administered, and nutritional support should be provided using elemental feeding or parenteral hyperalimentation.30 Use of anti-TNF agents is controversial in the treatment of severe Crohn's disease. Failure to respond or worsening symptoms may require surgical intervention.

PERIANAL AND FISTULIZING DISEASE

Suppurative conditions (abscess) are treated with drainage and should be jointly managed by gastroenterologists and surgeons. Chronic fistulae and perianal fissures are treated with antibiotics (metronidazole alone or in combination with ciprofloxacin), immunosuppressives, or anti-TNF agents.31 A placebo-controlled trial suggested benefits with infliximab in the closure of cutaneous Crohn's disease fistulae that had not responded to previous therapy with antibiotics, corticosteroids, or immunomodulators.11 No data are available from controlled trials concerning treatment by internal fistulae closure (enteroenteric, enterocolic, enterovesicular, and enterovaginal) with alternative immunomodulatory agents. Surgery may be considered.

Maintenance Therapy

Azathioprine is effective for maintenance of remission in patients with Crohn's disease (OR = 2.1; 95% CI, 1.4 to 3.5; NNT = 7).32 In a randomized controlled trial with 24 weeks of follow-up, 65 percent of patients maintained remission with methotrexate.33 Increasing evidence supports that “top-down” therapy beginning with infliximab and azathioprine may offer corticosteroid-sparing benefits for corticosteroid-naive patients.34 Evidence demonstrates that low-dose conventional corticosteroids and 5-ASA preparations are ineffective in maintaining remission in patients with Crohn's disease, and high-dose corticosteroids have not been evaluated as maintenance therapy.35,36 No published studies have evaluated antibiotics in the maintenance of remission. Budesonide is no more effective than placebo for maintenance of remission in patients with Crohn's disease at 12 months (RR = 1.13; 95% CI, 0.94 to 1.35; P = .19).37

Surgical Therapy

The most common indications for surgery include refractory disease, intractable hemorrhage, perforation, obstruction, abscess, dysplasia, cancer, and unresponsive fulminant disease. Patients with active luminal Crohn's disease that fails to improve within seven to 10 days of intensive inpatient medical management should be considered for surgery. The most common surgical procedures for Crohn's disease include surgical resection, stricturoplasty, and drainage of abscess. In a recent review of six population-based studies involving 25,870 patients with an average follow-up of 11.1 years, surgery was required in one-third of patients after corticosteroids were initiated, and the risk of postoperative recurrence over 10 years was 44 to 55 percent.38

In this study, one-half of all patients required surgery within 10 years of the diagnosis of Crohn's disease, and only 10 percent of patients had a prolonged clinical remission.38 Limited segmental resection is superior to subtotal colectomy in terms of fewer symptoms (P = .039), fewer loose stools (P = .002), and better anorectal function (P = .027).39 Postoperative infections are not associated with azathioprine, 6-mercaptopurine, or infliximab, but are associated with corticosteroid therapy.40 Stricturoplasty has been recommended in selected patients with small bowel disease to avoid impaired nutrient absorption, bile salt diarrhea, steatorrhea, bacterial overgrowth, and short bowel syndrome, but is not recommended for colonic disease.